B. Abstract and Specific Aims The goals of our center are to 1) elucidate the mechanical biology of T cells 2) use this understanding of T cell mechanical biology to develop novel T cell culture systems and engineered T cells for improved therapeutics. Adoptive immunotherapy overcomes many obstacles that limit vaccine strategies, by adoptively transferring T cells with controlled antigenic specificity. In addition, ex vivo culture of T cells allows for the generation of large numbers of T cells, which is of utmost importance in the face of T cell deficiencies in cancer. A major current challenge in adoptive immunotherapy is to control self-renewal potential of T cell, often referred to in immunology as memory, as it allows the immune system to maintain a higher frequency of T cells specific for pathogens encountered earlier. Another issue is self-renewal capacity in effector populations such as Th17 CD4 cells that are high effective in adoptive immunotherapy models. Hence, by engineering this property into T cells used in adoptive immunotherapy, both the immediate and long-term effects of therapy could be improved. Our NDC hypothesized that the IS integrates chemical and mechanical signals to determine the course of T cell differentiation. A major goal of our center is thus to improve immunotherapy by controlling the phenotype and function of ex vivo expanded T cells and in scalable numbers. We will focus on immunotherapy of cancers including both leukemias and solid tumors. Besides using adoptive immunotherapy to selectively and directly attack the tumor or tumor stroma, immunotherapy can be used to protect the patient from immunopathology resulting from treatment efforts. During treatment of leukemia by hematopoietic cell transplant (HCT), which aims at reconstituting the recipient with hematopoietic and immune cells post chemotherapy, donor T cells can cause graft-versus-host-disease (GVHD) - a significant source of morbidity and mortality post-HCT. Current approaches to prevent GVHD, which rely on the use of conventional drugs, and often lead to immunodeficiency, are not satisfactory and new GVHD preventive approaches are clearly needed. Therefore, within our goal of improving patient survival and quality of life, we also plan to make use of regulatory T cells (Tregs) to protect patients from the GVHD toxic effect by modulating Treg function and potency.